Abstract The aim of this study was to characterize the time course of maximal oxygen consumption ð _VO2 maxÞ changes during bedrests longer than 30 days, on the hypothesis that the decrease in _VO2 maxtends to asymptote. On a total of 26 subjects who participated in one of three bedrest campaigns without counter-measures, lasting 14, 42 and 90 days, respectively,
_
VO2 max maximal cardiac output ð _QmaxÞ and maximal systemic O2deliveryð _QaO2maxÞ were measured. After all periods of HDT, _VO2 max; _Qmax and _QaO2max were significantly lower than before. The _VO2 maxdecreased less than _Qmax after the two shortest bedrests, but its per cent decay was about 10% larger than that of _Qmax after 90-day bedrest. The VO_ 2 max decrease after 90-day bedrest was larger than after 42- and 14-day bedrests, where it was similar. The _Qmax and _QaO2max declines after 90-day bedrest was equal to those after 14- and 42-day bedrest. The average daily rates of the
_
VO2 max; _Qmaxand _QaO2maxdecay during bedrest were less if the bedrest duration were longer, with the exception of that of _VO2 maxin the longest bedrest. The asymptotic _VO2 max decay demonstrates the possibility that humans could keep working effectively even after an extremely long time in microgravity. Two compo-nents in the _VO2 maxdecrease were identified, which we postulate were related to cardiovascular decondition-ing and to impairment of peripheral gas exchanges due to a possible muscle function deterioration.
Keywords Bedrest Æ Exercise Æ Maximal oxygen uptake limitation Æ Maximal cardiac output Æ Maximal cardiovascular oxygen transport
Introduction
Maximal oxygen consumptionð _VO2 maxÞ is reduced by bedrest and its reduction is greater the longer the bedrest duration (Convertino1996). However, the time course of the _VO2 maxchange induced by bedrest is still unclear for two reasons: (1) most of the bedrest studies carried out so far lasted less than 1 month, which is insufficient to establish a time course of the _VO2 max change, and (2) very scarce data exist for repeated
_
VO2 max measurements at various times during bedrest on the same subjects, and only for bedrest duration of 20 and 30 days (Georgievskiy et al. 1966; Greenleaf et al.1989).
On the basis of a transversal analysis of data from bedrests lasting 7–30 days, Convertino (1996, 1997) proposed a linear decrease of _VO2 max with bedrest, with a daily rate of decay of about 1%. With such decay, however, _VO2 maxwould reach zero (100% loss)
C. Capelli (&) Æ G. Antonutto Æ M. Cautero Æ E. Tam Dipartimento di Scienze e Tecnologie Biomediche, School of Medicine, University of Udine,
P.le M. Kolbe 4, 33100 Udine, Italy e-mail: ccapelli@makek.dstb.uniud.it C. Capelli Æ G. Antonutto
M.A.T.I. Center of Excellence, University of Udine, P.le M. Kolbe 4, 33100 Udine, Italy
M. A. Kenfack Æ F. Lador Æ C. Moia Æ G. Ferretti De´partement de Physiologie,
Centre Me´dical Universitaire,
1 rue Michel Servet, 1211 Gene`ve 4, Switzerland G. Ferretti
Dipartimento di Scienze Biomediche e Biotecnologie, School of Medicine, University of Brescia,
V.le Europa 11, 25100 Brescia, Italy DOI 10.1007/s00421-006-0252-3
O R I G I N A L A R T I C L E
Factors determining the time course of _
VO
2 max
decay during
bedrest: implications for _
VO
2 max
limitation
C. Capelli Æ G. Antonutto Æ M. Azabji Kenfack Æ M. Cautero Æ F. Lador Æ C. Moia Æ E. Tam Æ G. Ferretti
Accepted: 8 June 2006 / Published online: 19 August 2006
within 122 days. This time interval is much shorter than the duration of long-term space missions. Thus, the change in _VO2max with bedrest duration cannot be linear, but must tend to an asymptote.
With this notion in mind, the aim of the present study was to gain a better understanding of the time course of the _VO2max changes in bedrests of duration longer than 30 days. The pursuit of this aim was made possible by having had the opportunity of measuring
_
VO2max and maximal cardiac output ð _QmaxÞ with the same protocols and procedures, after three bedrest campaigns, without countermeasures of increasing duration, up to 90 days.
Methods Subjects
A total of 26 healthy young male subjects were inves-tigated in three head-down-tilt (HDT, – 6 incline) bedrest experimental campaigns, lasting 14, 42 and 90 days, respectively. Their repartition in the three studies, and their anthropometric characteristics, referring to the pre-bedrest condition, are reported in Table1. None of the subjects underwent physical or pharmacological countermeasures during the bedrest period. None of the subjects were taking cardiovascu-lar medication at the time of the study and all subjects were non-smokers. The subjects underwent a cardio-pulmonary stress test during the selection process.
Study designs and methods were approved by the local ethical committee (Comite´ Consultatif de Pro-tection des Personnes dans la Recherche Biome´dicale, Toulouse) (90- and 42-day bedrest campaigns) and by the ethical committee of the School of Medicine of the University of Udine, Italy (14-day bedrest). All the subjects were informed about the aims of the investi-gation and the methods applied in the experiments and signed a written informed consent. The data obtained in occasion of the 42-day bedrest were previously published (but not those of the 14- and 90-day bed-rests) (Ferretti et al.1997).
Study design
Experimental campaigns were organized by the Euro-pean Space Agency in co-operation with national space agencies. The 42- and 90-day bedrest campaigns took place in Toulouse, France, the former at the Hoˆpital Purpan in 1994, the latter at the Clinique de l’Espace, Institut de Me´decine Spatiale, Hoˆpital Rangueil, in 2001–2002. The 14-day bedrest was organized in Cologne, Germany at the Aerospace Medicine Insti-tute and was completed over the biennium 2001–2002. Each bedrest consisted of three different phases: (1) baseline control experiments before bedrest; (2) a period of head down bedrest (–6) without counter-measure: no deviations from the lying position were permitted and neither exercise nor muscular contrac-tion tests were allowed during this period; (3) final experiments after bed rest. Exercise testing after bed-rest was performed on day 1, 4 and 3 after reambula-tion for the 14-, 42- and 90-day bedrests, respectively. For further details on the overall design of the three bedrests the reader is kindly referred to previous papers (Belin de Chanteme`le et al. 2004; Biolo et al. 2004; Ferretti et al.1997).
Protocol
An intermittent graded protocol for _VO2max determi-nation was used in the three bedrest campaigns.
_
VO2max was determined during graded exercise on the cycle ergometer. The lowest power was 50 W. Power was then progressively increased by 50-W steps. The step increase was reduced to 25 W as the individual maximum was approached. The lowest sub-maximal workloads lasted 7 min. As the workload increased, the exercise duration was reduced because the time spent for measuring _Q was shortened by increasing breathing rate. _VO2 and heart rate (fH) were determined at the
steady state, during the 6th minute of each work load. Steady-state _Q was determined immediately after the measurement of _VO2: Successive work loads were separated by 5 min recovery intervals, during which blood samples were taken at min 1, 3 and 5 for the determination of blood lactate concentration ([La]b).
Individual _VO2max was established from the plateau attained by the relationship between _VO2 and power above a given power. If such a plateau was not observed, subsidiary criteria for _VO2max establishment were (1) a lack of increase in fH between successive
work loads (DfH < 5 min–1); and (2) [La]b values
higher than 10 mM. The maximal aerobic power ð _wmaxÞ was then calculated as the minimal power requiring a _VO2 equal to _VO2max: The highest
Table 1 Anthropometric characteristics (mean ± SD) of the subjects participating in the study
Bed rest duration (days) n Age (years) Body mass (kg) Stature (cm) 14 10 24 ± 3.5 78 ± 7.7 182 ± 5.6 42 7 28 ± 1.0 74 ± 3.3 176 ± 1.0 90 9 32 ± 3.6 71 ± 5.4 173 ± 3.0
individual measured steady state _Q value was retained as the maximal cardiac outputð _QmaxÞ for that subject. This corresponded in all cases to a _Q value attained at the power requiring a _VO2 equal to _VO2max: The corresponding O2 flow in arterial blood (systemic O2
delivery at maximal exercise, QaO_ 2max) was then computed as described below.
Methods and techniques
Exercise was carried out either on an electrically braked cycle-ergometer (Ergometrics 800-S, Ergoline, Germany) (42- and 90-day bedrest) or on a mechani-cally braked ergometer (14-day bedrest) whose work load was independent of the pedalling frequency (Monark 839E, Sweden).
In the 42-day bedrest, _VO2 at rest and at exercise steady state was computed by standard expiratory mass balance equations. CO2outputð _VCO2Þ and pulmonary ventilationð _VEÞ were also calculated. During the 5th minute of each workload, expired gas was collected into Douglas bags and subsequently analysed for gas composition and volume. A paramagnetic O2analyser
(Oxynos 1-C, Leybold Haereus, Germany), an infrared CO2analyser (LB-2, Leybold-Heareus, Germany) and
dry gas meter (Singer DTM 15, Wellesley, MA, USA) were employed (Ferretti et al.1997).
In the 14- and 90-day HDT bedrest, breath-by-breath _VO2 was determined at alveolar level from respiratory gas fractions and ventilatory flow recorded at the mouth (Grønlund1984, Capelli et al.2001). N2,
CO2 and O2 fractions were measured in continuo by
means of quadrupole mass spectrometers (Airspec 2200, UK at Cologne, Balzers Prisma, Liechtenstein at Toulouse). Respiratory air flows were measured by means of ultra-sound flow transducers (Tuba, GHG, Switzerland at Cologne, and Spiroson, Eco Medics, Switzerland at Toulouse). Mass spectrometers and flow transducers were calibrated before and after each experimental run by means of certified gas mixtures and by means of a 3-l syringe, respectively (Hans Rudolph, Kansas City, MO, USA). The recorded data were digitalized by means of a 16-bit A/D converter (MP100 or MP150 WS, Biopac Systems, Santa Barbara, CA, USA) operated by a commercial soft-ware (ACK100W, Biopac Systems) running on PC. A computerized numerical procedure implemented under Labview environment (National Instruments, Austin, TX, USA) and running on PC was used to compute breath-by-breath _VO2 off-line. Resting and exercise steady-state _VO2 were then calculated by averaging breath-to-breath _VO2 values over 1 min.
The fH was monitored either by means of a
short-distance telemetry cardiotachometer (Polar 3000, Polar Electro, Finland) or by electrocardiography (Elmed, ETM, Germany).
In the 14- and 90-day bedrest studies, _Q was deter-mined by means of an open circuit acetylene technique (Barker et al.1999). To this aim, the subject breathed a gas mixture containing 21% O2, 6% He, 1.5% C2H2,
balanced with nitrogen until equilibration. Gas con-centrations while breathing the mixture were continu-ously monitored by mass spectrometry. Inspired and expired gas volumes were determined by the ultrasonic flow meters. The inspired gas mixture was adminis-tered from a high-pressure gas cylinder via 50 l Douglas bag buffers. The gas flow from the cylinders was adjusted to the subject’s ventilation. For each subject, the partition coefficient for acetylene was determined separately by mass spectrometry (Meyer and Scheid1980), on a 5 ml venous blood sample. The recorded data were digitalized as described before.
During the 42-day bedrest campaign, _Q was deter-mined from fHand stroke volume measurement (QH).
The latter was measured by means of the pressure-pulse contour method (Antonutto et al. 1995). To this aim, arteriolar blood pressure profile was continuously monitored by means of a Finapres device (Ohmeda, Englewood, CO, USA). The photo-plethysmographic cuff of the Finapres was applied to the middle phalanx of the middle finger of the right hand. The pressure profiles were recorded on a magnetic tape, digitalized (MP100 WS, Biopac Systems) and subsequently anal-ysed by a PC (ACK100W, Biopac Systems). Calibra-tion of the area described by blood pressure profiles was performed at rest, as previously described (Ferretti et al.1997).
Blood hemoglobin concentration ([Hb]) was mea-sured by a photometric technique (HemoCue, Sweden) on 10 ll blood samples from an earlobe. Arterial O2
saturation (SaO2) was measured by infrared oximetry
(Ohmeda 2350 Finapres, Englewood, CO, USA for the 42- and 90-day bedrests and Siemens MicrO2, Denvers,
MA, USA for the 14-day bedrest). _QaO2max was finally calculated as
_
QaO2¼ _QSaO2½Hbr ð1Þ
where constant r is the physiological O2 binding
coefficient of hemoglobin (1.34 ml g–1).
Blood lactate concentration in arterialized capillary blood was assessed by means of an electro-enzymatic method (ESAT 6661 Lactat, Eppendorf, Germany for the 42- and 90-day bedrests) or by means of a
colorimetric method (Accusport, Boeheringer, Ger-many for the 14-day bedrest).
Statistics
Mean values were reported along with their standard deviations (SD). Linear regressions were calculated by using the least square methods. Mean values before and after bedrest were compared by means of the non-parametric signed Wilcoxon rank test. Comparison of data among different bedrests was performed by means of the non-parametric Kruskall–Wallis test. When applicable, a Bonferroni post-hoc test was used to locate significant differences. The level of significance was set at P < 0.05 (two-tail test).
The time course of the change of _VO2max expressed relative to the values observed before bedrest set equal to 100%, was modelled as a function of bedrest dura-tion by means of a bi-exponential funcdura-tion describing the slow and fast component of the time course. The equation was of the form y = A1e(–t/s1) + A2e(–t/s2)
where A1and A2are the amplitude, s1and s2represent
the time constants of the fast and slow component, respectively. The parameters of the model were cal-culated by using an iterative, non-linear estimating
procedure (Carson et al. 1983) implemented in the statistical software Statistica for Macintosh (StatSoft, Tulsa, Ok, USA).
Results
The average values of all investigated parameters at maximal exercise, assessed before and after bedrests are reported in Table 2. Before bed rest, _VO2max was the same in the three studies. After all three bedrests,
_
VO2max decreased by about 14, 16 and 32% in com-parison with the pre-bedrest control values from the shortest to the longest bedrest. _wmax values were sig-nificantly lower than before bedrest and the decrease in _wmax was proportional to that in _VO2max: Cardiac output at maximal exercise ð _QmaxÞ dropped by 23, 30 and 23% after the three periods of bedrest. The aver-age values before and after the bedrests of 42 and 90 days were computed only on five out of seven and six out of nine subjects, respectively, since only in these cases it was possible to obtain, for technical reasons, both pre and post _Qmax data. The decrease in _VO2max was less than that in _Qmax after the two shortest bed-rests, whereas it was not the case after the 90-day
Table 2 Mean values ( ± SD) of maximal oxygen uptake ð _VO2maxÞ maximal cardiac output _QmaxÞ maximal heart rate
(fHmax) and maximal oxygen deliveryð _QaO2maxÞ together with
lactate concentration ([La]b), mechanical power ð _wmaxÞ
haemoglobin concentration ([Hb]) and per cent saturation of
oxyhaemoglobin (Sat[HbO2]) at _VO2maxbefore and after 14, 42
and 90 days of head down tilt bedrest. Significances of the differences between pre and post-bedrest conditions, (P values) and average values of per cent decrease are also reported
Parameter HDTBR Before After P Change (%)
_ VO2maxl min–1 14 2.80 ± 0.37 2.43 ± 0.31 < 0.05 – 13.9 ± 9.3 42 2.83 ± 0.20 2.36 ± 0.13 < 0.05 – 15.9 ± 5.4 90 2.81 ± 0.36 1.90 ± 0.31 < 0.05 – 32.4 ± 6.8 _ Qmax l min–1 14 25.3 ± 2.41 19.4 ± 3.04 < 0.05 – 22.8 ± 12.3 42 23.7 ± 2.42 16.4 ± 1.44 < 0.05 – 29.6 ± 5.0 90 19.7 ± 3.18 15.3 ± 2.16 < 0.05 – 22.7 ± 7.2 _
QaO2maxl min–1 14 5.6 ± 0.87 4.3 ± 0.86 < 0.05 – 22.6 ± 14.2
42 5.4 ± 0.77 3.5 ± 0.48 < 0.05 – 34.4 ± 5.6 90 4.3 ± 0.73 2.9 ± 0.22 < 0.05 – 29.8 ± 9.8 _ wmaxW 14 225 ± 27.6 175 ± 26.3 < 0.05 – 21.9 ± 10.2 42 229 ± 17.8 186 ± 11.3 < 0.05 – 17.8 ± 2.1 90 199 ± 25.0 136 ± 19.9 < 0.05 – 31.8 ± 8.1 fHmax, min–1 14 188 ± 3.8 183 ± 11.0 NS – 2.8 ± 5.7 42 194 ± 1.5 194 ± 2.3 NS – 0.4 ± 0.9 90 187 ± 6.5 188 ± 8.5 NS + 0.7 ± 1.9 [La]b, mM 14 11.9 ± 3.50 10.0 ± 1.54 NS – 9.3 ± 32.0 42 12.0 ± 0.57 11.2 ± 0.68 NS – 6.9 ± 3.4 90 10.1 ± 0.93 9.1 ± 2.15 < 0.05 – 6.9 ± 20.8 [Hb], g l–1 14 170.1 ± 2.7 166.5 ± 10.6 NS – 1.9 ± 5.3 42 173.3 ± 5.3 156.9 ± 4.9 < 0.05 – 9.3 ± 2.1 90 174.0 ± 9.2 159.6 ± 10.9 < 0.05 – 8.2 ± 7.0 Sat[HbO2], % 14 95 ± 0.4 97 ± 0.2 NS + 1.0 ± 0.05 42 94 ± 2.8 97 ± 0.8 < 0.05 + 3.3 ± 3.38 90 97 ± 0.4 98 ± 0.8 NS + 1.0 ± 0.04
bedrest. Observed per cent decreases of maximal oxygen delivery ð _QaO2maxÞ amounted to about 23, 34 and 30% from the shortest to the longest bedrest, respectively. After all three studies, maximal fH was
the same as before. [La]bafter maximal exercise at the
end of bedrest was equal to that before in the two shortest studies, yet it was significantly lower after the 90-day bedrest. [Hb] was significantly decreased after the two longest bedrests, although per cent saturation of oxyhaemoglobin (Sat[HbO2]) at maximal exercise
was identical before and after bedrests in all the cases. Thus, in these bedrests, the decrease in _QaO2max was larger than that in _Qmax:
The _VO2max decrease after the 42-day bedrest did not differ significantly from that after the 14-day bed-rest. The _VO2maxdecrease after the 90-day bedrest was significantly larger than that after the two other bed-rests. The same was the case for _wmax:The _Qmax and
_
QaO2max declines after the 90-day bedrest did not differ significantly from those after the 14- and 42-day bedrest. The greatest apparent _Qmax and _QaO2max de-creases were observed after the 42-day bedrest.
The average daily rates of the _VO2max; _Qmax and _
QaO2max decay during each of the three bedrests are shown in Fig.1. The average daily rate of _VO2max de-cline decreased from 0.99% per day for the 14-day bedrest, to 0.39% per day for the 42-day bedrest and to 0.35% per day for the 90-day bed rest. _Qmax and
_
QaO2max showed a faster average daily rate of decay than _VO2maxin the two shortest bedrests. For _Qmaxthis decay amounted to 1.63% per day for the 14-day bedrest, and 0.70% per day for the 42-day bedrest. For
_
QaO2max it amounted to 1.61% for the 14-day bedrest, and 0.82% per day for the 42-day bedrest. In the
lon-gest bedrest, the decay was 0.25% per day and 0.33% per day for _Qmax and _QaO2max respectively. The _Qmax and _QaO2max decreases appeared to be completed within 14 days.
In Fig.2the changes of _VO2maxexpressed relative to the values observed before bedrest set equal to 100%, are plotted as a function of the days of bedrest. The values computed from the present data are plotted together with those by Greenleaf et al. (1989) obtained at different times during bedrest on the same subjects, and with those taken from different sources in the literature (Convertino et al. 1982; Friman 1979; Georgievskiy et al. 1966; Kakurin et al. 1966; Kashi-hara et al. 1994; Saltin et al.1968; Smorawinski et al. 2001; Stremel et al. 1976; Taylor et al. 1949; Trappe et al. 2006, White et al. 1966). The bi-exponential function describing the changes of _VO2max as a func-tion of bedrest durafunc-tion was characterized by a fast component, with an amplitude of 10.2% and a time constant of 9.1 days, and by a slow phase, with an amplitude of 88.3% and a time constant of 327 days.
Discussion
In this study, _VO2max; _Qmax and _QaO2max were deter-mined for the first time after a bedrest as long as 90 days. The observed _VO2max decrease was 32.4%, which is larger than after the two shorter bedrests, but definitely less than predicted by a mere extrapolation from the percent changes in _VO2maxobserved after the 14-day bedrest. The same was the case for _Qmax and
Fig. 1 Average daily rates of decay of maximal oxygen uptake ð _VO2maxÞ maximal cardiac cardiac output ð _QmaxÞ and maximal
oxygen deliveryð _QaO2maxÞ observed after the 14, 42 and 90 days
of bedrest
Fig. 2 Changes of _VO2max expressed relative to the values
observed before bedrest set equal to 100%, as a function of bedrest duration in days. Full symbols refer to the values computed from the data obtained in the 14-, 42- and 90-day HDTBR; empty symbols refer to data collected from different sources in the literature (see text for more details)
_
QaO2max whose changes did not differ significantly with the bedrest duration from 14 days on.
The results of the present study demonstrate that the rate at which _VO2max decreases during bedrest becomes progressively smaller as the time of bedrest is prolonged. This is shown by (1) the similar _VO2max decrement after 14- and 42-day bedrests, and (2) the reduction of the average daily rate of _VO2maxdecrease with bedrest duration. The latter finding indicates that most of the _VO2max decrease occurs within the first 2 weeks of bedrest, the remainder taking place slowly and progressively toward the 90th day.
Greenleaf et al. (1989) reported data of _VO2max obtained on four subjects at days 7, 14, 21 and 29 of bedrest. Despite the small number of subjects, and despite the fact of having been obtained in supine rather than upright posture, their data compare well with the present ones. The greatest average daily rate of _VO2max decrease in their study occurred during the 1st week of bedrest (–1.37% per day), to slow down progressively in the following weeks. Their figure for the _VO2max change on day 14 (–10.7%) was similar to that observed in the present study for the same bedrest duration (–13.9%, see Table2).
These findings suggest the _VO2max decrease with bedrest tends toward an asymptote, as hypothesized. Thus, they contradict the concept of a linear _VO2max decrease with time during bedrest proposed by Convertino (1996, 1997). They rather suggest the possibility of attaining and likely maintaining steady, but low _VO2max values during very long sojourns in microgravity. Similarly, the changes in Q_max and
_
QaO2max from the present study showed a more marked decrease during the early phase of bedrest, with a clear tendency to slow down and stabilize for longer bedrest duration. Indeed, the percent changes of
_
Qmax and _QaO2max were the same after all three bed-rests.
Our postulate is that the fast component of the _
VO2max decrease during bedrest is related to the reduction of _QaO2max consequent to the reduction of both _Qmax and [Hb], whereas the slow component accompanies the impairment of peripheral gas ex-change, likely associated, at least in part, to the development of muscle hypotrophy.
In a previous paper (Ferretti et al. 1997), it was demonstrated that the decrease in _VO2max due to bedrest results from the simultaneous action of at least two factors: the decrease in cardiovascular oxygen transport, and the decrease in muscle oxidative capacity, which parallels the decrease in muscle mass. It is now clear that these two factors follow different time courses during bedrest. In fact a transversal
analysis of the CSA data from different sources in the literature (Ferretti 1997) and of the present subjects after the 42- and 90-day bedrests (Ferretti et al. 1997; Trappe et al. 2004), provided a calculated time con-stant of CSA decay (128 days) that was much slower than that for _Qmax and _QaO2max :in fact in the present study both these parameters underwent only minor changes after only 14 days of bedrest. On this basis it is legitimate to postulate that the time course of the
_
VO2max changes during bedrest ought to be charac-terized by at least two components, one fast related to changes in _QaO2max the other slow, dictated by the decrease in muscle oxidative potential. Thus, in this study, the decrease of _VO2max expressed as relative change of the initial value set equal to 100%, was modelled by means of a bi-exponential model with no time delays. The bi-exponential model was character-ized by larger r2 than the simpler mono-exponential model (0.69 vs. 0.61), its residuals distribution was closer to normality and showed a smaller standard deviation (4.5 vs. 4.6) than that of the mono-expo-nential model. Both these statistical results support the postulate behind the present analysis. Whereas the calculated time constant of the fast component accu-rately described the time course of the cardiovascular changes induced by bedrest, the time constant of the slow component turned out to be about 11 months long, that is some two and half times more than the calculated time constant for muscle CSA (see above). The paucity of reliable data on long-term bedrests, and its restriction to a time span of less than 90 days implies that the value of the slower time constant estimated on this occasion resulted from extrapolation rather than interpolation of data, and thus should be considered with a pinch of salt. However, despite to these intrinsic limitations, modelling the _VO2max changes by using a complex time course seems to be legitimate and sug-gests a multifactorial set of causes for the observed decay of the maximal aerobic power.
Yet the strongest argument in favour of a multifac-torial origin of the _VO2max decrease during bedrest comes from an analysis of the factors that limit _VO2max (di Prampero 1985; di Prampero and Ferretti 1990). The algebraic solution of this model, for the case in which only the cardiovascular resistance to oxygen flow (RQ) is changed, is given by the following equation :
_
VO2max=ð _VO2maxþ D _VO2maxÞ ¼ 1 þ FQðDRQ=RQÞ ð2Þ where FQ is the fractional limitation to VO_ 2max imposed by cardiovascular oxygen transport. Equa-tion 2 implies that the ratio between the absolute
_
related to the relative change in RQ, the y-intercept
being equal to 1 and the slope to FQ. This relationship
for the present data is shown in Fig.3, where the ratio DRQ/RQ is estimated from the changes in _QaO2max: The individual values from the three bedrests are superimposed to the theoretical line for FQ = 0.7 (di
Prampero and Ferretti1990). Whereas the values after the 14- and 42-day bedrests are symmetrically distrib-uted around the theoretical line, the values for the 90-day bedrest are displaced upward with respect to the theoretical line. Likewise, an analysis of residuals, ob-tained as the difference between theoretical and actual
_
VO2max decays for the corresponding changes in RQ,
shows that the theoretical line is a fairly good predictor of the data obtained from the 14- and 42-day bedrests (residuals equal to – 0.002 ± 0.153 and – 0.050 ± 0.165, respectively, both being not significantly different from 0), but not of those from the 90-day bedrest (residuals equal to 0.333 ± 0.248, P < 0.05). Since the theoretical line applies to _VO2max changes induced by a modifi-cation of a single resistance to oxygen flow, the discor-dance between this line and the data obtained after the 90-day bedrest indicates that additional factors beyond cardiovascular oxygen transport are to be taken into account to explain the observed decay in _VO2max:
Assuming that the lungs do not limit _VO2max in healthy subjects who do not desaturate at sea level (di Prampero and Ferretti 1990), the overall limitation of
_
VO2max is imposed by cardiovascular oxygen transport, which sets RQ, and by peripheral oxygen diffusion and
utilization, setting the peripheral resistance (Rp)
in-series with RQ. The overall resistance to oxygen flow
downstream the lungs (RTOT) is thus equal to :
RTOT¼ RQþ Rp¼ ðFQRTOTÞ þ ðFpRTOTÞ ð3Þ where Fpis the fractional limitation to _VO2maximposed by peripheral (muscular) factors. In turn,
RTOT¼
ðPaO2 PmO2Þ _
VO2 max
ð4Þ where PaO2 is arterial O2 partial pressure (assumed
equal to 100 mmHg after 42-day bedrest, see Ferretti et al. 1997, and unchanged for longer bedrest dura-tion), and PmO2 is the O2 partial pressure in the
mitochondria, assumed equal to 0 (in fact lower than 3 mmHg, see Connett et al. 1986; Richardson et al. 1999,2001). FQand Fpwere calculated after the 42-day
bedrest (Ferretti et al.1997), and turned out to be 0.73 and 0.27, respectively. Since the decrease in _QaO2max was the same after the 42- and 90-day bedrests, and since the _QaO2max before bedrest was the same in all investigations (see Table2), it follows that RQshould
be the same after the 42-day as after the 90-day bed-rest. On this basis, combination of Eqs. 3 and 4 allows an estimate of Rpafter the 90-day bedrest:
PaO2 _ VO2max90 ¼ FQ42 PaO2 _ VO2 max42 þ Rp90 ð5Þ
where subscripts 42 and 90 indicate the bedrest duration. Since _VO2max was lower after 90-day than after 42-day bedrest, but the O2gradient was the same, RTOT, and
thus Rpmust be higher in the former than in the latter
case. This is demonstrated in Table3, where the RTOT,
RQ and Rp for the 90-day bedrest, calculated by
intro-ducing in Eq. 5 the experimental mean values of the present study and the value assumed for PaO2, are
compared with the corresponding values after the 42-day bedrest. These values carry along a different fractional limitation of _VO2max after the 90-day bedrest with re-spect to the 42-day bedrest. In fact FQ decreased from
0.73 to 0.59, whereas Fp increased from 0.27 to 0.41.
These changes in FQand Fpmean that the impairment of
peripheral gas exchange, which develops during very long bedrest, may have increased the role of peripheral (muscular) factors in limiting maximal aerobic power.
Fig. 3 Changes in maximal oxygen consumption ( _VO2max
expressed as the ratio between the values before and after bedrest) as a function of the calculated relative changes in the cardiovascular resistance to _VO2max(RQ). Data refer to the three
bedrest campaigns, as indicated (14 days, n = 10, 42 day, n = 5, 90 day, n = 6). The line is theoretical and has a slope of 0.70, corresponding to the fractional limitation imposed by the cardiovascular system (FQ) reported by di Prampero and Ferretti
(1990) for humans at sea level. Whereas the points for the 14-and 42-day bedrest lie around the theoretical line, the data for the 90-day bedrest do not: in this case the change in _VO2maxis
These results have important practical implications for future long-term space missions because (1) the tendency toward an asymptote of the _VO2max decay demonstrates the possibility for humans to keep working effectively even after extremely long time in microgravity, and (2) specific muscular training ought to be added to countermeasures for the cardiovascular system for the entire duration of very long bedrests or space flights in order to counteract the slow decay of maximal aerobic power. Both these aspects should be taken into account in programming a future human mission to Mars.
Acknowledgments This research was supported by the Italian Space Agency grant ASII/R/300/02 to Carlo Capelli and by the Swiss National Science Foundation Grants 31-64267.00 and 3200B0-102181 to G. Ferretti. The long-term bedrest study 2001– 2002 was organized by the European Space Agency, together with the Centre National d’Etudes Spatiales and the Japanese National Space Development Agency. The Short Term Bed Rest-Integrative Physiology campaign 2001–2003 was organized by the European Space Agency, together with the German Space Agency (DLR). Many thanks to all of the very dedicated staff at the MEDES Institute for Space Medicine and Physiology in Toulouse, France and at the Institute of Aerospace Medicine of DLR, Germany. In particular, we greatly acknowledge the co-operation of Dr. Marie-Pierre Bareille, Dr. Alain Maillet, Dr. Jacques Bernard, Dr. Martina Heer and Dr. Andrea Boose. The authors are very grateful to the volunteers for their excellent dedication to the study. We heartily thank Dr. Pietro Enrico di Prampero for having discussed with us the ideas and concepts that contributed to the success of the paper.
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